Activated granulocytes and inflammatory cytokine signaling drive T-cell lymphoma progression and disease symptoms

Abstract

Peripheral T-cell lymphomas (PTCL) - especially angioimmunoblastic (AITL) and follicular TCL - have a dismal prognosis due to lack of efficient therapies, and patients` symptoms are often dominated by an inflammatory phenotype including fever, night sweats, weight loss and skin rash. In this study, we investigated the role of inflammatory granulocytes and activated cytokine signaling on PTCL-TFH (T-follicular helper type) disease progression and symptoms. We show, that ITK-SYK driven murine PTCLs and primary human PTCL-TFH xenografts both induce inflammation in mice including murine neutrophil expansion and massive cytokine release. Granulocyte/lymphoma interactions were mediated by positive autoregulatory cytokine loops involving INF-γ (CD4+malignant T-cells) and IL-6 (activated granulocytes), ultimately inducing broad JAK kinase activation (Jak1/2/3, Tyk2) in both cell types. Depletion of inflammatory granulocytes via antibodies (Ly6G), genetic granulocyte depletion (LyzM-Cre/MCL1flox/flox) or the deletion of IL-6 within microenvironmental cells blocked inflammatory symptoms, reduced lymphoma infiltration and enhanced mouse survival. Furthermore, unselective JAK kinase inhibitors (ruxolitinib) inhibited both, TCL progression and granulocyte activation in various PTCL mouse models. Our results support the important role of granulocyte-driven inflammation, cytokine-induced granulocyte/CD4+ TCL interactions and the requirement of an intact JAK/STAT signaling pathway for PTCL-TFH development, and support broad JAK kinase inhibition as an effective treatment strategy in early disease stages.

Targeting the cGAS‐STING Pathway Inhibits Peripheral T‐cell Lymphoma Progression and Enhances the Chemotherapeutic Efficacy

“…[ 37 ] Moreover, autoregulatory cytokines, including IFN‐γ (secreted by CD4+ malignant T cells) and IL‐6 (secreted by activated granulocytes), could mediate granulocyte‐lymphoma interaction, thereby triggering inflammatory symptoms, enhancing lymphoma infiltration and affecting the survival of patients with PTCL. [ 38 ] Similarly, increased serum IL‐10 levels predict poor survival and early recurrence in patients with PTCL. [ 39 ] An elevated C‐reactive protein level, a crucial marker of inflammation, also has a poor independent prognostic value in patients with AITL.…”

HIV-1 Structural Proteins or Cell-Signaling Factors? That Is the Question!

“…In summary, gp120’s role in HIV infection extends beyond viral entry, influencing various cellular processes and contributing to the complexity of HIV pathogenesis. The inflammatory pathways STAT3, NF-κB, and PI3K/AKT, activated by gp120 in cells of the immune system, directly or indirectly alter the microenvironment, producing a tumor microenvironment and favoring the development of lymphomas [ 66 , 67 ].…”

The RNA sequencing results revealed the expression of different genes and signaling pathways during chemotherapy resistance in peripheral T-cell lymphoma

“…This disease primarily manifests in extranodal sites such as the intestinal tract, skin, lymph nodes, spleen, and other tissues outside of the bone marrow. Common symptoms include fever, night sweats, weight loss, itching, and other systemic manifestations [ 1 , 2 ]. The specific etiology of PTCL has not been determined and various risk factors have been identified for its development.…”